p-siletanylbenzylidene acetal: Oxidizable Protecting group for diols

Article abstract of DOI:10.1021/jo052015r

Hydrogen peroxide oxidation of benzylidene acetals (and derivative benzyl ethers) that incorporate a siletane ring at the para position creates a deprotection pathway without affecting other important chemical properties of the benzylidene acetal, such as

Full text of DOI:10.1021/jo052015r

SCHEME 1. Synthesis and Reductive Opening of PSP
Acetal 3
p-Siletanylbenzylidene Acetal: Oxidizable
Protecting Group for Diols
Sarah E. House, Kevin W. C. Poon, Hubert Lam, and
Gregory B. Dudley*
Department of Chemistry and Biochemistry, Florida State
UniVersity, Tallahassee, Florida 32306-4390
gdudley@chem.fsu.edu
ReceiVed September 26, 2005
efficient glycosylations yet cleave under mild and mutually
compatible conditions.
The p-siletanylbenzyl (PSB) ether fulfills the criteria neces-
sary to meet this demand.2 It is electronically similar to the
benzyl ether and stable to the DDQ-promoted removal of the
p-methoxybenzyl group, yet treatment with hydrogen peroxide
or tert-butyl hydroperoxide (TBHP) under Tamao-type condi-
tions7 triggers its cleavage. However, siletanes succumb to ring-
opening reactions in the presence of hard nucleophiles such as
alkyllithiums and potassium or sodium alkoxides.8 Silver oxide-
promoted arylmethylation reactions do not affect the siletane
functionality; this provides a convenient method for the forma-
tion of PSB ethers from primary alcohols, but secondary alcohols
reacted sluggishly in our initial study. We therefore became
interested in alternative methods for preparing PSB ethers from
secondary alcohols.
Hydrogen peroxide oxidation of benzylidene acetals (and
derivative benzyl ethers) that incorporate a siletane ring at
the para position creates a deprotection pathway without
affecting other important chemical properties of the ben-
zylidene acetal, such as regioselective reductive ring opening.
Herein we describe the synthesis and utility of p-siletanyl-
benzylidene acetal 1, which presents one option for introducing
PSB ethers onto secondary alcohols in a manner consistent with
many synthetic efforts. In a broader context, the p-siletanyl-
phenyl (PSP)-substituted acetals provide an attractive comple-
ment to other alkylidene acetal PGs for the unique cleavage
pathway enabled by peroxide oxidation of the arylsiletane
moiety. Thus, in the course of developing PSP-substituted
acetals as precursors to PSB ethers, we were also interested in
(1) verifying that the chemistry of arylsiletane-derived acetals
(e.g., 3) is grossly analogous to other widely studied benzylidene
acetals and (2) highlighting the primary difference in chemical
reactivity, which is the ability to oxidize the arylsiletane moiety
to the corresponding phenol with hydrogen peroxide. In this
Note we report the results of our studies aimed at addressing
these points, and we submit the p-siletanylbenzylidene acetal
(1) as a novel reagent for the protection of diols.
Our recent finding1 that alkyl- and arylsiletanes are oxidized
to the corresponding alcohols with alkaline peroxide under mild
conditions prompted a follow-up study, in which the p-
siletanylbenzyl (PSB) ether was designed and tested as a
protecting group (PG) for alcohols and phenols.2 Protecting
group manipulations play a key role in organic synthesis.3 We
envision particular applications of the PSB group in carbohy-
drate synthesis.4
Arylmethyl ether PGs are routinely employed in glycosyla-
tions due to their tolerance of acidic reaction conditions and to
exploit their increased reactivity relative to acyl-protected
glycosyl donors.5 Frequently the spectator hydroxyl groups
require differential protection; for such cases there is a demand
for diverse arylmethyl (modified benzyl) PGs6 that support
The para-siletanylbenzylidene acetal undergoes reductive ring
opening upon treatment with diisobutylaluminum hydride
(DIBAL-H) to afford the more substituted PSB ether. We
examined the protection of 1,3-butanediol and subsequent
reductive ring opening of benzylidene acetal 3 (Scheme 1).
Simple acetal formation occurred quantitatively with use of
catalytic camphorsulfonic acid (CSA) in refluxing methylene
chloride. Note the arylsiletane stability to acidic conditions.
Subsequent treatment with DIBAL-H9 afforded 4 in nearly
quantitative yield; the overall yield for the two-step sequence
(1) Sunderhaus, J. D.; Lam, H.; Dudley, G. B. Org. Lett. 2003, 5, 4571-
4573.
(2) Lam, H.; House, S. E.; Dudley, G. B. Tetrahedron Lett. 2005, 46,
3283-3285.
(3) (a) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley and Sons: New York, 1999. (b) Kocienski,
P. J. Protecting Groups, 3rd ed.; Thieme: Stuttgart, Germany, 2003.
(4) PreparatiVe Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel
Dekker: New York, 1997.
(5) The armed/disarmed tactic for glycoside coupling takes advantage
of this reactivity difference. (a) Mootoo, D. R.; Konradsson, P.; Udodong,
U.; Fraser-Reid, B. J. Am. Chem. Soc. 1988, 110, 5583-5584. (b) Paulsen;
H.; Richter, A.; Sinnwell, V.; Stenzel, W. Carbohydr. Res. 1978, 64, 339-
362.
(6) For recent arylmethyl PGs that were developed within the context
of carbohydrate synthesis, see: (a) Jobron, L.; Hindsgaul, O. J. Am. Chem.
Soc. 1999, 121, 5835-5836. (b) Plante, O.; Buchwald, S. L.; Seeberger, P.
H. J. Am. Chem. Soc. 2000, 122, 7148-7149.
(7) Tamao, K.; Ishida, N.; Ito, Y.; Kumada, M. Org. Synth. 1990, 69,
96-105.
(8) Sheikh, R. K.; Tharanikkarasu, K.; Imae, I.; Kawakami, Y. Macro-
molecules 2001, 34, 4384-4389.
10.1021/jo052015r CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/19/2005
420
J. Org. Chem. 2006, 71, 420-422

SCHEME 2. PSP Acetal and PSB Ether in a Carbohydrate
System
SCHEME 4. Oxidative Activation of a PSP-Substituted
Acetal
SCHEME 5. Synthesis of Arylsiletane-Based Protecting
Group Reagents
SCHEME 3. Oxidative Activation/Deprotection of a PSB
Ether
(2 f 4) was 97%. This goes toward addressing the difficulty
we had in preparing PSB ethers from secondary alcohols;2 it
also illustrates behavior that parallels other benzylidene acetal
PGs.
acetals, which are generally stable to mildly oxidizing reaction
conditions.3 The resulting p-hydroxyphenyl (PHP)-substituted
acetal (9) is thereby activated for cleavage (by analogy to the
PHB ether).13,14 The PSP-substituted acetal thus provides a
useful complement to other common diol PGs.
PSP reagent 1 is conveniently prepared in one step from the
commercially available reagents 10 and 11 (Scheme 5).
Furthermore, hydrolysis15 and reduction of 1 affords PSB-OH
(13), which we disclosed previously for the protection of
alcohols and phenols.2 This alternative synthesis of 13 (and by
extension, PSB-Br 14) is significantly less expensive than our
previously reported procedure.
Several notable findings resulted from this study:
1. p-Siletanylphenyl (PSP)-substituted acetals can be formed
and reductively ring opened in analogy to other common
benzylidene acetals, which introduces the PSB ether onto
secondary alcohols in a manner consistent with many synthetic
efforts.
2. PSP-substituted acetals are oxidized with mildly alkaline
hydrogen peroxide, conditions that are highly unlikely to affect
typical acetal PGs.
We next investigated p-siletanylphenyl (PSP)-substituted
acetals within a carbohydrate framework. Glucose-derived diol
510 was protected as shown in Scheme 2, and the PSP-substituted
acetal (6) was subjected to reductive ring opening with DIBAL-
H. As is the case with the parent benzylidene acetal,11 regio-
selectivity for this process was high, though not perfect. By
employing an excess of DIBAL-H and maintaining a cold
reaction temperature,12 PSB ether 7 was isolated in 81% yield.
In this manner, the PSB ether was installed onto the free
secondary hydroxyl of 5.
In previous studies, we found that siletanes can be oxidized
to alcohols in the presence of silyl (i.e., TBS) ether PGs and,
conversely, that siletanes are stable to the acidic hydrolysis of
TBS ethers.1 Similarly, the oxidative cleavage of PSB and PMB
ethers is mutually compatible: DDQ (2,3-dichloro-5,6-dicyano-
1,4-benzoquinone) selectively removes the PMB group, whereas
alkaline hydrogen peroxide affects only the PSB ether.2 Cleav-
age of the PSB ether protecting group from the carbohydrate
substrate is depicted in Scheme 3.
3. PSB reagents 13 and 14 are now available at a reduced
cost by way of PSP acetal 1.
We are continuing our efforts in this area; further synthetic
applications of the arylsiletane oxidation will be reported in due
course.
Oxidation of the arylsiletane moiety incorporated within PSB
ether 7 afforded a metastable intermediatesthe p-hydroxybenzyl
(PHB) ether, R ) PHBsthat was easily decomposed to reveal
the free alcohol (5, Scheme 3).13 This finding is entirely
consistent with our previously reported studies on the depro-
tection of PSB ethers.2
Experimental Section
Alkylidene 6 is oxidized under identical conditions (Scheme
4). This stands in sharp contrast to other common alkylidene
4-(1-Methylsiletanyl)benzaldehyde Dimethyl Acetal (1). Mag-
nesium turnings (146 mg, 6.00 mmol) and iodine (21 mg, 0.080
mmol) were placed in an oven-dried, two-neck, round-bottom flask
with a stir bar under argon. THF (1.5 mL) was added, followed by
1,2-dibromoethane (50 µL, 0.32 mmol). The mixture was then
cooled to 0 °C in an ice bath for 10 min. 1-Chloro-1-methylsila-
cyclobutane (0.34 mL, 2.8 mmol) was added dropwise. A solution
(9) Siletanes withstand DIBAL-H but decompose in the presence of
lithium aluminum hydride.
(10) Prepared in two steps and 93% overall yield. See the Supporting
Information.
(11) Mikami, T.; Asano, H.; Mitsunobu, O. Chem. Lett. 1987, 2033-
2036.
(12) The reaction vessel was placed in the freezer overnight. See the
Supporting Information.
(13) p-Hydroxybenzyl (PHB) ethers are moderately stable to isolation
and purification, but they break down readily under a range of conditions
including DDQ (CH2Cl2, 0 °C), FeCl3 (Et2O, 20 °C), NaOMe (MeOH, 60
°C), etc.; see ref 6a.
(14) For example, iron trichloride in ether is effective. See the Supporting
Information.
(15) The conversion from 1 to 12 is essentially quantitative, but our
starting material (1) was contaminated with a small amount of 12 from
incidental hydrolysis that had occurred upon prolonged storage.
J. Org. Chem, Vol. 71, No. 1, 2006 421

of 4-bromobenzaldehyde dimethyl acetal (350 µL, 2.1 mmol) in 5
mL of THF was then added dropwise over 45 min via a pressure-
equalizing addition funnel at 0 °C. The reaction mixture was stirred
at 0 °C for 1 h and at room temperature overnight, quenched with
5 mL of water, and extracted with three 5-mL portions of diethyl
ether. The combined organic layers were washed with 5 mL of
brine, dried (MgSO4), filtered, and concentrated under reduced
pressure. Purification by column chromatography on silica gel (10%
ethyl acetate in hexanes) provided 0.450 g (91%) of 1 as a colorless
oil. 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J ) 7.8 Hz, 2H), 7.46
(d, J ) 7.8 Hz, 2H), 5.40 (s, 1H), 3.34 (s, 6H), 2.19 (q, 2H), 1.35-
1.12 (m, 4H), 0.55 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 139.2,
139.0, 133.4, 126.2, 103.1, 52.7, 18.2, 14.3, -1.77. HRMS (EI+)
found 236.1235 (calcd for C13H20O2Si 236.1233).
Acknowledgment. This research was supported by the FSU
Department of Chemistry and Biochemistry. S.E.H. is the
recipient of the Brautlecht Fellowship for summer undergraduate
research and H.L. received a two-year postdoctoral fellowship
from the MDS Research Foundation. We thank Dr. Joseph
Vaughn for assistance with the NMR facilities, Dr. Umesh Goli
for providing the mass spectrometry data, and the Krafft Lab
for the use of their FT-IR instrument. We thank Dr. Kaustav
Biswas for helpful discussions.
Supporting Information Available: Detailed experimental
procedures, characterization data, and NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO052015R
422 J. Org. Chem., Vol. 71, No. 1, 2006